JPS61186316A - Plaster for external use - Google Patents

Abstract

PURPOSE:A plaster having raised biological use ratio of drug, capable of grasping accurately dosage of drug, easily usable, obtained by blending a drug with water-soluble protein having promoting action on absorption, a polyhydric alcohol, an adhesion imparter, and an oily substance. CONSTITUTION:Preferably (a) 0.05-5wt% drug such as drug of circulatory organs, nervous system, endocrine system, etc. is blended with (b) 10-30wt% water-soluble protein (e.g., gelatin, solubilized collagen, casein, etc.), (c) 10-30wt% polyhydric alcohol (e.g., glycerin, propylene glycol, etc.), (d) 0.5-20wt% adhesion imparter (e.g., cellulose, cellulose, polysaccharide, etc.), and (e) 0.5-15wt% oily substance (e.g., fatty acid ester, lanolin oil, etc.). A soft plaster for external use (soft patch) having skin adhesion by itself. Addition of the water-soluble protein provides improved endermic absorption. The plaster is produced industrially advantageously.

Description

[Detailed description of the invention] The present invention relates to an external patch.

Conventionally, pharmaceutical preparations applied to the skin include ointments, liquids,
Poultices, tapes, and the like are known, but these preparations have problems in setting an appropriate dose of the drug, release and permeability of the active ingredient, bioavailability, feeling of use, etc. For example, in the case of ointments, it has been pointed out that the exact dosage of the drug depends on the area and thickness to which it is applied, and that systemic effects due to transdermal absorption cannot be expected. Furthermore, in comparison with other oral administration methods, external preparations still have problems such as the skin acting as a barrier to drug absorption and extremely low bioavailability. On the other hand, although a new administration form called a drug delivery system has recently been developed, it has yet to be put into practical use for a small number of specific drugs.

Considering the above technical situation, the authors of this project 8A conducted extensive research with the aim of solving the problems in the conventional technology and developing the next topical preparation, and found that a topical preparation containing water-soluble protein has excellent percutaneous absorption. As a result of further investigation based on this knowledge, we have developed the present invention as an easy-to-administer and use external preparation that increases the bioavailability of the drug and allows accurate determination of drug dosage. I ended up completing it.

In order to achieve the above-mentioned objective of slow growth, such a preparation of the present invention contains specific ingredients mainly consisting of water-soluble proteins.

That is, the external patch of the present invention contains the following components (a)t
(b) A soft topical patch (hereinafter referred to as
(sometimes abbreviated as "soft patch").

(a) Drugs: Water-soluble proteins that promote absorption (c) Polyhydric alcohols (d) Adhesive agents (e) Oily substances The above drugs are particularly restricted if they can be absorbed transdermally. However, such drugs include both locally applied drugs and systemically applied drugs. Topically applied drugs are used to treat cutaneous and subcutaneous diseases, or to adjust the skin condition to protect the skin, and are mainly drugs that exert their medicinal effects locally. Can be mentioned. In addition, examples of drugs that are applied systemically include drugs that are absorbed through the skin surface where they are applied, reach tissues, organs, etc. in the body through the blood, and mainly exert systemic medicinal effects.

These drugs affect the circulatory system, nervous system, endocrine system, respiratory system,
These include drugs that affect the metabolic, urinary, and digestive systems, antimicrobial agents, antitumor agents, vitamins, diabetes drugs, enzymes, and Chinese herbal medicines or crude drug extracts. More specific examples of these are as follows.

■Analgesic and anti-inflammatory agents: acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, colicol salicylate, l-menthol, camphor, mefenamic acid, flufenamic acid.

indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen,
furanoprofen, fenoprofen, salindac,
Fenbufen, Clidanac, Flurbiprofen, Indoprofe/, Futisic acid, Fentiazac, Tolmetin, Tiaprofenic acid, Benzadac, Fufuexamac.

Piroxicam, phenylbutacin, oxyphenbutacin, clofazone, pentazocine, meperizole, etc.;
■Steroidal anti-inflammatory agents: Noridroco-f17, glednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, fludrocortiscin acetate, etc.: ■Antihistamines or antiallergic agents: chlorpheniramine, glycyrrhizic acid, diphenhydramine, periactin ■Local anesthetics - penzocaine, procaine, dibucaine, lidocaine, etc.;■
Antimicrobial agents, etc. (including antibacterial agents, antifungal agents, antifungal agents, and antiviral agents) such as tetodicyclines such as nioxytetracycline, penicillins such as ampicillin, cephalosporins such as cephalothinato, kanamycin, etc. Macrolides such as aminoglycosides and erythromycin.

Chloramphenicol, iodo compound m, nitrofurantoin, nystatin, amphotericin, fradiomycin, sulfonamides, virolnidoline, clotrimazole, etc.; Antihypertensive agents: clonidine, α-methyldopa, reserpine, syrosingobine, recinamine, cinnarizine, Hydralazine, prazosin, etc.; ■ Antihypertensive diuretics: theofmylin, trichloromethiazide, furoseked, tripacid, methyclothiazide, penflucito, noidrothiazide, spironolactone, metolazone, etc.; ■ Cardiac drugs: digitalis, ubidecarenone, dopamine, etc.; ■ Coronary vasodilators: Nitroglycerin, isosorbitol cinitrate, erysto-stetranitrate, pentaerytol tetranitrate, diviridamol, dirazep 4, trapidil, trimetazidine, etc.; O vasoconstrictors: dihydroergotamine, dihydroergotoxin, etc.; 0 β-blocker or Antiarrhythmic drugs: Vindolol, Gloplanol, etc.; O Calcium antagonists and other cardiovascular drugs: Diltiazem, Nifedipine, Nicardipine, Benzi (Mil, Bendicran, Ibuenprodil tartrate 9molsidomine, etc.); O Antiepileptic drug Nitrazenocum , meprobamate, phenylene, etc.;O
Anti-vertigo agents: isoprenaline, betahistine, scopolamine, etc.; 0 tranquilizers: diazenocum, lorazeno(mu), flunitrazepam, fluphenazine rx;
Cyfrobarbital, etc.; Q muscle relaxants:) Riperisone, baclofen, dantrolene sodium, cyclobenzapyrine, etc.; Autonomic nerve agents, niatropine, levodopa, etc.; ■Respiratory agents: codeine, ephedrine,
Isoproterenol.

Dextromethorphan, orsibrenaline, ibratrobium proside, cromoglycic acid, etc.; @hormone or antihormonal agents: corticothrobin, oxytocin, vasopressin, testosterone, phlogesterone, estradiol, salivary gland hormones, thyroid hormone, adrenal hormone, kallikrein, Insulin, oxendrone; @vitamins: vitamins A, B, C, D, g
.

K and its derivatives, calciefferols, mecoparamine, etc.; @Anti-tumor agents: 5-fluorouracil and its derivatives, krestin, picibanil, ancitabine, cytarabine, etc. ro#s: lysozyme, urokinase, etc.; θ Chinese herbal medicines or herbal medicine extracts: licorice, aloe,
Purple root, etc.; 0 anti-ulcer agents niarantoin, ardioxa,
Alcloxa, N-methylscopolamine methyl sulfate, etc.; @ antidiabetic agents, etc.

Two or more of the above drugs can be used in combination, if necessary. In addition, the above drugs are used in the free state, and those that can be salt-formed are in the form of acid or base salts, and in the form of carbo/base salts.
Those having acid groups can be used in the form of their esters.

The acids mentioned above include organic acids (e.g. methanesulfonic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, acetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid), and as bases. Examples include organic bases (eg, ammonia, triethylamine) and inorganic bases (eg, sodium hydroxide, potassium hydroxide). Further, examples of the esters include alkyl esters, aryl esters, aralkyl esters, and the like.

Among these, drugs that act on the circulatory system, nervous system, endocrine system, respiratory system, etc., antimicrobial agents, enzymes, and the like are particularly preferably used as the drugs of the present invention.

As mentioned above, the present invention can be applied to all kinds of drugs, but among such drugs, transdermal absorption is particularly rare or very slight when used alone. Drugs that have a low bioavailability when administered orally (e.g., drugs with a bioavailability of less than 80%), drugs that have many side effects, and drugs that are broken down by digestive juices, etc., so the administration method must be injection. This effect is most pronounced in drugs that are susceptible to the first-pass effect in the liver, etc.

The amount of the above-mentioned drug to be mixed may be as long as it is sufficient for the expression of the drug's efficacy, and in most cases, it is 0.01 to 15% of the total formulation.
It is blended in an amount of α05 to 10% by weight, more preferably 0.05 to 5% by weight. The dose may be increased or decreased as appropriate depending on the type of drug, therapeutic purpose, patient's age, weight, degree of disease progression, etc.

The above-mentioned water-soluble protein is not particularly limited as long as it exhibits an absorption promoting effect on the drug to be mixed. Such water-soluble proteins are natural or non-natural proteins, and examples of natural proteins include animal proteins and vegetable proteins, and examples of non-natural proteins include artificially obtained peptides. Although there are technical fields in which peptides are distinguished from proteins, in the present invention they are included in proteins from the viewpoint of their effects.

Specific examples of the above animal proteins include gelatin, solubilized collagen, casein (or sonosodium salt),
Examples include glue and their hydrolysates. This gelatin and solubilized collagen include soluble proteins obtained by hydrolyzing proteins contained in animal bones, skins, etc. with acid or alkali or by treating them with hot water, and also by appropriate chemical modification ( Examples: succinylation, maleylation, phthalation).
Its molecular weight is about 1 to 100,000.

In addition, the above-mentioned vegetable proteins include soybean proteins (e.g., those obtained by precipitating and enzymatically treating the water-soluble portion of defatted soybean soapstock).
, soybean casein is an alternative. Furthermore, the above-mentioned peptides can be produced by chemically synthesizing the same kind of amino acids or from amino acids.
It includes peptides obtained by condensation by fermentation, semi-synthetic means, etc., and the molecular weight thereof is usually in the order of several hundred to several hundred. Therefore, the constituent amino acids of this peptide are:
Neutral, basic and acidic amino acids; optically active forms and 2
Semi-form; various amino acids such as natural and synthetic amino acids can be employed. In the present invention, one or more of the above water-soluble proteins are used.

For example, gelatin alone or a mixture of gelatin and casein or soybean protein can be used.

Furthermore, among the water-soluble proteins listed above, gelatin, solubilized collagen, casein, soybean protein, etc. are generally preferred, taking into account drug absorption promoting action, compatibility or dispersibility with other ingredients, difficulty in obtaining them, etc. used as.

The amount of the above-mentioned water-soluble protein may be sufficient to achieve the object of the present invention, and preferably, an amount sufficient to promote drug absorption through the skin. For this purpose, water-soluble protein is often used in an amount equal to or higher than that of the drug;
~50% by weight.

Preferably 5-35% by weight, more preferably 10-30%
It is blended in an amount of about % by weight.

Examples of the polyhydric alcohols include those having 2 to 6 alcoholic hydroxyl groups. That is, glycols, triols, and polyols having 4 to 6 alcoholic hydroxyl groups are included. Specific examples of the glycol include:
Glycols having 2 to 6 carbon atoms (e.g. ethylene glycol,
7'a? "Lengericol, butylene glycol), polyethylene glycol (average molecular weight = 200 ~ &
000, preferably about 200 to 6,000), etc.
Preferred examples of the triol include glycerin, tri-propane, and methylolpropane, and examples of the polyol include sorbitol.

One or more of these polyhydric alcohols may be used; for example, glycerin alone or a mixture of glycerin and butylene glycol may be used.

Among the polyhydric alcohols mentioned above, adjusting and maintaining the softness of the topical patch of the present invention, compatibility with other ingredients or dispersibility,
Various materials can be used without particular limitation as long as they suit the purpose of ensuring wettability during application, but among them, those with low volatility and plasticity are generally preferred, and in this sense, glycerin, Glopylene glycol, butylene glycol, sorbitol and the like are preferably used.

The amount of the above-mentioned polyhydric alcohols cannot be absolutely limited, as it varies depending on the purpose of blending and the type of other ingredients.
Usually 5 to 50% by weight, preferably 5% by weight based on the total formulation.
It is blended in an amount of about 35% by weight, more preferably about 10 to 30% by weight.

As the above-mentioned tackiness imparting agent, a substance is used which imparts tackiness to the skin to the preparation itself. As such an adhesion agent, it is preferable to use an agent that has functions such as imparting adhesion to the skin, maintaining the viscosity of the preparation itself, and preventing volatilization of other components such as moisture by forming a film on the surface of the preparation. These include polyvinyl pyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, and polyvinylpyrrolidone.

The above celluloses have an average molecular weight of 40,000 to 20
Specifically, alkylcellulose and hydroxyalkylcellulose in which the alkyl moiety in one structural unit has 1 to 4 carbon atoms (e.g., methylcellulose, ethylcellulose, flobylcellulose, methylpropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose) , hydroxypropyl starch)
, carboxymethyl cellulose or its alkali metal salts.

Specific examples of the above polysaccharides include starch and its derivatives (
Examples: carboxymethylated starch, hydroxypropyl starch); single polysaccharides such as dextrin, dextran, chitin, alginic acid or its sodium salt, glycogen, pullulan (trade name, Taishu Co., Ltd.), carrageenan, etc.; mannan.

Examples include complex polysaccharides such as pectin, gum arabic, gum karaya, and xanthan gum.

The carboxyvinyl polymer has an average molecular weight of 9
00,000 to 3,000,000,000,000 to about 3,000,000, and includes polyacrylic acid, polymethacrylic acid, and alkali metal salts thereof, and more specifically, Hibis Wako ■ (trade name, manufactured by Wako Tsumugi Pharmaceutical), Carbo Ball ■ (product name, manufactured by Gutdrich, USA), Rubiscoll ■ (product name, West Germany, BA
Commercially available products such as BF (manufactured by BF) are advantageously used. One or more of the above tackifiers may be used.

In the present invention, when using the above-mentioned tackifier, the amount to be blended is selected to be an amount that can achieve the above-mentioned purpose of blending, and is usually 0.1 to 15% by weight, preferably 0.1 to 15% by weight based on the entire formulation. .3-10% by weight, more preferably 0.5-1
It is about 0 weight.

The above-mentioned oily substances include fatty acid esters, aliphatic higher alcohols, paraffin oil, and lanolin oil.

Examples include silicone oil and Plastipase (trade name, Squibb & Sons, Inc.).

The fatty acid esters mentioned above are esters of aliphatic carboxylic acids and aliphatic alcohols, and may be either synthetic or natural products. As the aliphatic carboxylic acid,
Contains saturated or unsaturated aliphatic mono(di)carboxylic acids, specifically lower or higher fatty acids having 2 to 24 carbon atoms, and among them, fatty acids having 6 to 20 carbon atoms.
Intermediate to higher fatty acids are often employed as preferred. Specific examples include: acetic acid, propionic acid, hexanoic acid, capric acid, caprylic acid, octanoic acid, dioctanoic acid, adipic acid, sepacic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, lyrinic acid, myristic acid.

The aliphatic alcohols include saturated or unsaturated aliphatic monools and triols having 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms, and polyols having 4 to 8 hydroxyl groups. Specifically, the monool includes linear or branched alcohols, such as methanol, ethanol, glopanol, butanol, hexanol, octatool, decanol, hexadecanol, octyldodecyl alcohol, palmityl alcohol, and stearyl. Typical examples of the triol include glycerin, and typical examples of the polyol include sorbitol and monosaccharide. The above-mentioned ester of aliphatic carboxylic acid and aliphatic alcohol is preferably one in which all the carboxylic acid groups and alcoholic hydroxyl groups in the molecule participate in ester formation (complete ester), but in some cases, One of the groups in the aliphatic dicarboxylic acid molecule, the carboxylic acid group or (and) a part of the hydroxyl group in the tri(poly)ol molecule may be free (partial ester). It may also be a mixed acid group ester.

Among them, intermediate to higher fatty acids with 6 to 20 carbon atoms (
Tri)glycerides, complete esters of intermediate to higher fatty acids having 6 to 20 carbon atoms and aliphatic monools having 1 to 20 carbon atoms, or partial esters of polyols are preferably used. Specific examples of the above fatty acid esters are shown below: isopropyl myristate, octyldodecyl myristate, myristyl myristate, isopropyl palmitate, butyl stearate, decyl oleate, diisopropyl adipate, diethyl sepatate,
Hexyldecyl dioctoate, sorbitan monopamitate, monosaccharide fatty acid ester, triacetin, caprylic di(tri)glyceride.

Capric acid di(tri)glyceride, mixed acid group triglyceride consisting of caprylic acid and capric acid, oleic acid di(tri)glyceride,
tri)glyceride, linoleic acid di(tri)glyceride,
A mixed acid group triglyceride consisting of oleic acid and linoleic acid.

The above-mentioned fatty acid esters can be used either in a pure or almost pure state, such as in synthetic products, or in a state in which other substances are mixed, as in natural products. A specific example of the former is:
The above-mentioned substances may be used as they are, and specific examples of the latter include natural fats and oils, such as pork fat,
Animal oils such as beef tallow and spermaceti and vegetable oils such as soybean oil, sesame oil, cottonseed oil, coconut oil, olive oil, castor oil and beeswax may be used.

° The above aliphatic higher alcohol has 14 to 14 carbon atoms.
Typical examples include 20 saturated or unsaturated aliphatic alcohols, such as cetanol (palmityl alcohol), stearyl alcohol, oleyl alcohol, and hexadecyl alcohol.

The above paraffin oil is mainly a paraffin mixture having 15 or more carbon atoms, specifically liquid paraffin,
(White) Vaseline, squalane.

Examples include squalene, among which liquid paraffin,
White petrolatum, squalane, etc. are often used as preferred.

Examples of the silicone oil include polymerized mixtures of dimethylsiloxane (eg, dimethylpolysiloxane) and alkyl esters thereof, methylphenylpolysiloxane, and glycolmethylsiloxane.

Examples of the lanolin oil include lanolin, lanolin wax, hydrogenated (reduced) lanolin, and its ethylene oxide polymer rg, among which lanolin is often used as the preferred one.

The chemical composition of this lanolin is usually as follows: 30-35% by weight of alcohols (e.g. cetyl alcohol, lanolin alcohol, carnaravir alcohol); cholesterins (e.g. cholesterin, incholesterin, metacholesterol). 1Jy) 15-20% by weight; fatty acids (e.g.
Acetic acid, butyric acid, caproic acid, myristic acid, stearic acid, lanostearic acid) 45-55% by weight, etc.

Among the above-mentioned oily substances, those having the effect of further promoting transdermal absorption of the drug, the effect of further increasing the solubility of the drug, and having less skin irritation are preferably used. Most of these oily substances are in the form of liquid or paste, and in some cases waxy, and can be used without any problem in either state, and it is usually convenient to use commercially available products.

In the present invention, one or more of the oily substances listed above can be used.

The amount of the above-mentioned oily substance to be blended is selected to meet the purpose of the present invention, and is usually 0.1 to 25% of the total formulation.
% by weight, preferably about 0.5 to 20 weight-1, more preferably about 0.5 to 15 weight-1.

Furthermore, in addition to one or more ingredients, an appropriate amount of water may be added in order to maintain the formulation properties of the soft patch, such as softness and drug absorption. In this case, the blending amount is usually 20 to 80% by weight, preferably 30% by weight, based on the entire formulation.
The amount is about 75% by weight, more preferably about 35-70% by weight.

In addition to the above-mentioned components, other substances may be added as necessary in order to more effectively express the characteristics of the soft batch. Known additives can be used as such additives. A specific example is shown below.

■ Absorption aids (those that play an auxiliary role in drug absorption, such as promoting the softening of the stratum corneum, improving water retention or water absorption, or expanding the upper pores): Urea, Salocol, 1-n-dodecyl azocyc-a-butan-2-one [product Name Niashin ■ (*zone)
(manufactured by Nerlin Research and Development Company, USA)], dimethyl sulfoxide, dodecyl sulfoxide, dimethyl formamide, dimethyl acetamide, toluic acid diethylamide, tetrahydrofurfuryl alcohol, dodecylpyrrolidone, 2-pyrrolidone, methylpyrrolidone, allantoin, salicylic acid, etc. . When these absorption aids are used, the amount added is usually about 0.05 to 5% by weight, preferably about 0.1 to 5% by weight of the entire formulation.

■Preservatives (those with functions such as preventing deterioration caused by microorganisms and preservatives): paraoxybenzoic acid alkyl ester (
halapenes), sorbic acid, dehydroacetic acid, etc. When these preservatives are used, the amount added is usually 0.05 to 2% by weight, preferably 0.1 to 1% by weight of the entire formulation.

■Emulsifier/dispersant (those with functions such as uniform dispersion of compounded ingredients): polyoxyethylene fatty acid ester, polysorbate) 80 Nonionic surfactants such as R, IH, etc.
7-ion surfactants such as sodium lauryl sulfate, lower alcohols such as ethanol.

such as acetone. When using these emulsifying and dispersing agents,
The amount added is usually O, Q5~a, O
% by weight, preferably about 0.1 to 3% by weight.

■pH adjusters (those that mainly have the functions of stabilizing ingredients, alleviating skin irritation, or maintaining drug absorption by adjusting pH): Organic acids (e.g., citric acid,
Tartaric acid, milk rR) 7:l: Inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid) or alkali metal salts thereof. When the pH adjuster is used, the amount of the pH adjuster may be sufficient to maintain the desired 9H level, and is usually 0.00% of the total formulation.
The amount is about 1 to 5% by weight, preferably about 0.5 to 5% by weight.

■Colorants: Water-soluble tar pigments, natural pigments, etc.

In addition, in the present invention, there is no need to use a crosslinking agent (eg, an aldehyde compound) or an astringent (eg, zinc oxide, kaolin) as in conventionally known gelatin poultices. Their use may actually impair the softness of the formulation.

The shape of one dosage form of the soft patch composed of the above ingredients may be any size and shape that can be easily applied to the skin surface, and is generally plate-shaped, disc-shaped,
Preferably, it is in the form of a strip, a thin film, or the like, and has an appropriate thickness and area (effective area in contact with the skin surface when applied).

In this case, the appropriate thickness is usually about 0.2 to 3 cm, preferably about 0.3 to λ01111, and the area is usually about O,OS to 200 crd, preferably 0.2 to λ01111. 160c! ! That's about it. That is,
For example, if it is a plate-shaped soft batch, its length x width is usually 0.2 x 0.4 to 10 x 20 cm.
, preferably 0.4 x 0.5 cm to 10 x
In addition to being able to be of the order of 16 cIL, it is also possible to adopt a disc-shaped, band-shaped, etc., and a cone of the size of a cone within the above-mentioned area range. Which shape to adopt among these shapes is arbitrarily selected depending on the administration site, therapeutic purpose, etc.

Soft patches having the above shape are generally separated into individual dosage forms, but in some cases, for convenience of use, a cutting groove is provided to distinguish one dosage form. In the form of a large plate that can be used several times or several dozen times, or a strip wound into a roll so that the required amount can be cut off with scissors etc. during use. It can be done.

In order to use, store, and handle the above-mentioned soft patch, if one or both sides of the soft patch are covered with a suitable packaging film, the packaging film can be removed at the time of use and the exposed drug side can be attached to the skin. It is often useful to keep yourself busy. Therefore, the soft patch can be constructed in the following forms: 1) without any packaging film; 2) with a packaging film on one side; 2) with a packaging film on both sides. Such packaging films include synthetic resin films (e.g., polyethylene films, polypropylene films, nystomer films, butadiene polymer films, isoprene polymer films), cellophane films, etc. with a thickness of about 0.02 to 0.8 mm. It is preferable to use a fabric that is stretchable, but woven or non-woven fabric may also be used.

In addition, it is recommended to store the soft patch in a bag made of fabric containing volatile components or a paper bag with moisture-proof treatment.

The external patch of the present invention is generally soft.

Specifically, it has flexibility and viscoelasticity, as evidenced by its softness that allows it to be slightly deformed without damage to its shape.For example, it can be easily deformed by applying some external force. It can be expanded, contracted, and dented (therefore, it adheres well to the skin and feels good when used).

Incidentally, cases where the softness of the preparation is increased by moistening the surface of the soft batch with water during application are also included in the concept of softness in the present invention.

The soft patch having the above-mentioned structure is applied to the skin of various parts of the body for medical purposes depending on the treatment purpose, target, etc. For example, for topical application, it is applied directly to or near the diseased area, and for whole body application, it is applied to areas where it is easy to absorb the active ingredient through the skin (e.g., areas where keratin is not developed or where there is little discomfort). It is best to apply it to the affected area.Also, it can be used for cosmetic purposes (for example, to prevent rough skin and sunburn) by incorporating known cosmetic ingredients.

Various methods can be used to produce the soft patch as long as they do not impede the purpose of the present invention.

For example, it is used by adding an appropriate modifier to the conventional means used for manufacturing pharmaceutical preparations such as layer agents, chewing gums, jellies, confectionery such as thiolate, and foods such as noodles. The modi vacancies are modi vitae that are required to maintain softness and improve drug absorption, which are the objectives of the present invention. As a typical manufacturing method, a method of molding to a size of is adopted. Specifically, (a) ■ a mixture of water-soluble protein and water; ■ a mixture of drugs, polyvalent a~・-, -□* (at this time,
(Add the above-mentioned additives as necessary); and ■ Prepare a mixture of the tackifier and water, and then mix step by step in the following order until the entire preparation has uniform properties. It is often convenient to use the process of stirring until the mixture is mixed and then forming the mixture.

In this molding process, the drug substance obtained in this process is usually spread into a container with an appropriate thickness and size, or compression molded using an appropriate frame. It may be subdivided into the size of a single dosage form by operations such as cutting or punching. Other manufacturing methods include (b) using other liquid components (e.g., polyhydric alcohols) in place of water, or (c) blending with or without adding water. A method may be adopted in which the components are crushed or kneaded and then compressed and molded in a suitable mold.

During or after the above steps, the above-mentioned packaging film can be applied as necessary. In the above manufacturing method,
Because it consists of simple and convenient operations and processes, it is advantageous for implementation on an industrial scale, and it is possible to obtain soft patches in various shapes and forms depending on the purpose, and it is also easy to incorporate into conventional solid preparations. It is possible to incorporate even liquid or low-melting point drugs that have been difficult to incorporate.

Examples of the method for producing the external patch of the present invention are shown below. In addition, the formulation of each example is shown in the first barley.

Example 1 (Clidanac-containing preparations below, the drugs contained are shown in the same way) According to the prescription in Table 1, ■ 15 g of gelatin was added to purified water so
■Pullulan■
19 and 1 g of polyvinyl alcohol) with purified water 17.
Dissolved in 7 J: ■ Sodium polyacrylate 65
g Dissolved in 10 g of purified water; ■ 23 g of glycerin, 0.59 diisoprobyl adipinate and polysorbate)
Clidanac 19 and 0.1 g of parabens were suspended in a mixture of 800.2p while heating at 50°C;
was added and stirred in a homomixer at the same temperature;
was added and stirred in a homomixer at the same temperature;
was added, stirred in a homomixer at the same temperature, and then spread to one thickness on a polyethylene packaging film in a deafening device, and then cut to produce a plate-shaped soft patch with 6 scratches in the vertical direction and 4 cIL in the horizontal direction.

Example 2 (Pindolol-containing preparation) According to the formulation in Table 1, a drug substance obtained in the same manner as in Example 1 was molded into a strip having a thickness of IIIX@λOcm. After applying a packaging film to this product, it was wound into a coil.

Example 3 (Clidanac-containing preparation) According to the prescription in Table 1, by the same method as Example 1,
Each obtained drug substance is 1 m thick x 13 cm long.
It was molded into a plate shape of 10 cm x 10 cm.

Example 4 (Preparation containing ibenprodil tartrate) Purified water 3λ31 according to the prescription shown in Table 1! 2 g of sodium citrate was dissolved in the solution, 20 g of gelatin and 2 g of pullulan were added thereto, moistened, and then dissolved under heating at 50°C. (2) Sodium polyacrylate O, S, @ was dissolved in 5I of purified water. (2) 5g 1C of Polysolvay 80 was dissolved in purified water. (2) Ibuenprodil tartrate and 3 g of white petrolatum were uniformly mixed with 23 g of glycerin while heating at 50°C. ■While heating to 50℃ in a homomixer, first add ■ and ■ to ■, then add ■ to this,
Finally, (2) was added, and after sequential stirring, the mixture was spread in a molding machine. After cooling, cut into pieces, Length x Width x Thickness = 6.5 cm
X 6.5 am Xα4■ thin film-like soft patch (this product contains iaenprodil tartrate 2039)
was manufactured.

Examples 5 to 22 (preparations containing ibuempazyl tartrate) Target soft patches were manufactured in the same manner as in Example 4 based on the formulations shown in Table 1.

In addition, in Example 7, the obtained drug substance was punched and cut to a thickness x diameter = 0.4 x 30 m.
In Example 9, a soft patch in the form of a round film was formed into a tape shape with thickness x width = 0.4cm x λ5aIL, and a wrapping film (made of polyethylene) was applied to the soft patch in the form of a coil. A rolled product was manufactured. In other Examples, soft hatches having the same or similar configuration as Example 4 were manufactured.

Examples 23 to 27 (Preparations containing clonidine hydrochloride) Based on the formulation shown in Table 1, the drug substance obtained according to the same method as Example 4 was cut, and length x width x thickness = 2 cm
A thin film-like soft patch (containing 0.319 clonidine hydrochloride) measuring 2 cm x 0.4 dew was prepared.

Examples 28 to 33 (fedipine-containing preparations) Target soft patches were manufactured according to the same method as in Example 4 based on the formulations shown in Table 1.

Examples 33 to 35 (prazosin hydrochloride-containing preparations) Based on the formulation shown in Table 1, the drug substance obtained according to the same method as Example 4 was cut, and the length x width x thickness = 2 tx
A company that manufactures a thin film-like soft patch (this product contains pranon hydrochloride 7187) measuring 4 m x 2 cm x Q.

Examples 36 to 40 (Clidanac-containing preparation) In Example 36, according to the formulation shown in Table 1,
09 and 2 fl of Pluruff were moistened with 41.31i of purified water and dissolved under heating at 50°C; ■ Glycerin 23.9
0.21 of parabens was dissolved under heating at 50°C; ■ Sodium polyacrylate α59 was dissolved in 5 g of purified water; ■ Polysolva) 80 Lli was dissolved in purified water 511; ■ Diisoprobyl adipine ) 0.5 g of Clidanac was added to 1.59 and dissolved under heating at 50°C. ■
While heating to 50° C. in a homomixer, first, ①, ② and 4 were added to ②, then ③ was added thereto, and after sequentially stirring, the mixture was spread in a molding machine. Thereafter, the desired soft patch was manufactured in the same manner as in Example 4.

In Examples 37 to 40, soft patches for this purpose were manufactured in the same manner as in Example 36 according to the formulations shown in Table 1.

Examples 41 to 47 (Pindolol-containing preparations) Target soft patches were manufactured in the same manner as in Example 36 based on the formulations shown in Table 1.

Examples 48 to 51 (preparation containing propranolol hydrochloride) In Example 48, based on the formulation shown in Table 1,
■Dissolve 3y of sodium citrate in 20.9ml of purified water,
20 I of gelatin was added to this, moistened, and dissolved under heating at 50°C; ■ 10 I of sodium caseinate was added to 10 I of purified water.
Dissolved in g;■ Parabens 0.2 in 20g glycerin
1 was added, dissolved under heating in 50 tl, and added to methylcellulose "g"; ■Polysolvay) 80 1
g was dissolved in purified water 59. 1; ■ 0.959 of propranolol hydrochloride was dissolved in the remaining purified water; ■ A mixture of 1 g of Stuff 2F and 3I octyldodecyl myristate was heated to 50°C; ■ Under heating at 50°C in a homomixer First, ■, ■, and ■ were added to ■, then 5 was added thereto, and finally ■ was added. After sequentially stirring, the mixture was spread in a molding machine. Following the same method as in Example 4, the desired soft patch was manufactured.

In Examples 49 to 51, target soft patches were manufactured in the same manner as in Example 4B according to the formulations shown in Table 1.

Examples 52 to 56 (preparations containing isosorbitate nitrate) In Example 52, based on the formulation shown in Table 1,
■Add 30g of purified water to 20.9g of gelatin and moisten it,
Dissolved under heating at 0°C; ■ Added 0.2.9 of parabens to 10 g of glycerin, dissolved under heating at 50°C, cooled, added and suspended Karaya gum 2I; ■ Polysorbate 80 1, 9 in 5 g of purified water; ■ 1.25 g of insorbitol nitrate was suspended in sorbitol 59 and the remaining purified water; ■ Squalane 4.51 was heated to 50°C; ■ To 50°C in a homomixer. While heating, first
Add ■ and ■ to this, then add ■ to this, and finally ■
were added, sequentially stirred, and then spread into a molding machine. Thereafter, the desired soft patch was manufactured in the same manner as in Example 4.

In Examples 53 to 56, target soft patches were manufactured in the same manner as in Example 52 according to the formulations shown in Table 1.

Examples 57 to 59 (Preparation containing N-methylscopolamine methyl sulfate) In Example 57, according to the formulation shown in Table 1,
■Gelatin 20. 30g of purified water was added to li+ to moisten it, and it was dissolved under heating at 50°C; ■ 10g of carrageenan 191C purified water was added and swollen; ■ 0.211 of parabens was added to 20.9% glycerin and heated at 50°C. Dissolved; ■ Polysorbate 801y was dissolved in 5 JilVC of purified water; ■ N-methylscopolamine methyl sulfate 0.09
Si was dissolved in the remaining purified water; ■3 g of silicone oil
and 2 g of squalane were mixed and heated to 50°C; ■ While heating to 50°C in a homomixer, first add ■, ■, and ■ to ■, then add ■ to this, and finally add ■, sequentially. After stirring, the mixture was spread into a molding machine. Thereafter, the desired soft patch was manufactured in the same manner as in Example 4.

In Examples 58 to 59, target soft patches were manufactured according to the same method as in Example 57 based on the formulations shown in Table Ii1.

Examples 60 to 61 (Piroxicam-containing vehicle) Target soft patches were manufactured in the same manner as in Example 4 based on the formulations shown in Table 1.

The external patch of the present invention obtained by the above method can be stored in a stable state, and when used, has appropriate adhesion and adhesiveness to the skin and mucous membranes of the human body. It is also comfortable to use, does not cause any side effects such as rash even if applied for a long time, and can be easily removed after use. The vehicle of the present invention has the following characteristics and is therefore very useful medically and industrially.

(a) It is easier to use than conventional topical preparations such as ointments, and the dosage can be easily determined. Therefore, the occurrence of side effects and loss of drug due to overdosage.

Since it is possible to avoid underdosing and underachieving drug efficacy, it is possible to take appropriate measures according to the therapeutic purpose and target disease.

(b) Excellent transdermal absorption of active ingredients such as drugs is provided. Therefore, not only local efficacy but also systemic efficacy is expected.

(c) Since it is a soft preparation, it has good elasticity, good adhesion to the skin, and good feel when used.

(d) Drugs that have problems with side effects (gastrointestinal disorders, etc.) and physiological usability using other administration methods such as oral administration can be effectively improved (delayed metabolism, etc.).

(e) If you are taking oral doses several times a day, you may forget to take one dose.

The patch of the present invention can be used if you dislike taking it, or if you need to take it in various types or in large amounts.

It has a long-term medicinal effect when used once or twice a day, is easy for patients to use, and is easy for doctors to manage both the disease and the drug's efficacy.

Next, a test example of a formulation of the present invention will be described.

Test Example 1 (Sensory test regarding feeling of use such as adhesion and stickiness) The soft patch of Example 4 from which the drug was removed was used as a sample, and "New Edition Sensory Test Handbook" pages 356 to 366 (published by Japan Science and Technology Association) was used. Based on Scheffe's method as described,
The test was conducted twice on each subject for 10 adults. That is, the above sample was applied to the left and right upper arms, and removed after 2 hours.
The comfort was judged based on the following criteria: Very good - (+3
), certainly good 1/'AC+2 ), somewhat good (+
1), the difference is Nagomi (0),, somewhat bad In (-1).

Definitely Bad (-2), Very Bad (-3).

As a result, the usability of the above soft patch was +2.04±0
．． It was 78. For reference, a commercially available poultice that was tested at the same time had a value of -0.73±0.83. Furthermore, in addition to these results, subjects pointed out that the soft patch had a particularly soft feel, which was not found in conventional external patches.

Test Example 2 (Serum concentration at the time of ibenprodil tartrate administration) (Method) White male domestic rabbits (1 group: 3 rabbits, body weight: 3.1-4.
3 kg) was shaved using electric clippers to avoid damaging the skin on the day before administration of the sample, and the following external preparations (c) to (I) of the present invention were applied to the shaved area. Separately, for comparison, an external preparation (B) that does not contain fats and oils and an oral preparation (
A) was prepared and used.

The doses for these dermal and oral administrations are each 1°/kl in terms of ibenprodil tartrate! Met.

(A) 0.15% ibenbrozil tartrate aqueous solution.

(B) The true method of this external preparation is as follows: ■ 20 g of gelatin
was moistened with 30 g of purified water and dissolved under heating at 50°C.

(2) Pullulan 5I was dissolved in 10 g of purified water. (2) Glycerin 23I, 0.2 g of parabens and 1 g of ibenprodil tartrate were added to 10.89 g of purified water and mixed thoroughly while heating to 50°C. (2) While heating to 50° C. in a homomixer, (2) was first added to (1), then (2) was added thereto, and after sequentially stirring, the mixture was spread in a molding machine. After cooling, cut
A thin film-like soft patch with length x width x thickness = 6.5α x 6.5α x 0.4 cm was manufactured. (c) Soft patch of Example 10.

CD) Soft patch of Example 11.

(E) Soft patch of Example 12.

(F) Soft patch of Example 13.

(G) Soft patch of Example 14 @ (H) Soft patch opening of Example 15 CI) Soft patch of Example 16.

In the case of the above specimens (A) and CB) administration group, after administration 01
From 25 to 8 hours, or for 2 to 30 hours after administration in the case of the specimens (c) to (J) administration groups, 3.5 to 4 blood samples were collected at appropriate times, and serum was fractionated by centrifugation. Each 2zILl of this serum was extracted with ether, the extract was reacted with pentafluorobenzylbromide in the presence of a strong alkali, and then the derivative obtained by reacting with bis(trimethylsilyl)trifluoroacetamide was subjected to EC.
The amount was determined using a D-gas chromatography device (63Hl, GLC-4CM type manufactured by Shimadzu Corporation).

(Results) The results of the above experiment are shown in Table 3. The results revealed the following: Oral administration (A) of ! : Comparison soft patch (B) showed an AUC (serum lower concentration) value of about 172. ■Soft patches (c) to (1), which are made by adding oils and fats to this CB), have a higher blood concentration and persistence than the above (A) and (B), and have high bAU.
In particular, soft patch CG) 2 showed a Cmax (maximum serum concentration) about 4 times higher and an AUC value about 24 times higher than those of (A) above.

Test Example 3 (Serum concentration during administration of piroxicam-containing preparation) (Method) SD male and female rats 1 group 3 rats 1 body weight 250
A portion on the dorsal nucleus of ~290,1 it) was shaved.

The following specimens (A) and CB) were pasted or applied to this shaved area (area 3×3 crIL=9 cit).

The amount of sample administered at this time was converted to the amount of piroxicam, which was 0.5
1n9/boiled.

(A) Soft patch of Example 60.

(B) Known preparation: A piroxicam-containing ointment described in JP-A-59-13714, consisting of the following formulation: piroxicam 0.5. p, Hibiswako ■105 l,
Ol, diisopropaturamine 1.3I, glycerin 2, p, 1.3-butylene glycol 51, ethanol sag and purified water 60.2.9° (1980) 9 published by the Japanese Society of Rheumatology]. Similarly, serum piroxicam concentration was determined by fluorescence method (measurement wavelength: 370 nm).

(Results) The results of the above experiment are shown in Table 4. Table 4: Serum pyrobasicum concentration (9 m1/m &> Based on the results 1) The formulation of the present invention has an AU of approximately 2.7 times that of the known formulation.
It was found that the drug exhibited increased transdermal absorption of the drug.

Claims (1)

[Claims] The following components (a), (b), (c), (d) and (e)
), and has its own skin-adhesive properties. (a) Drugs (b) Water-soluble proteins that exhibit an absorption-promoting effect (c) Polyhydric alcohols (d) Adhesive agents (e) Oily substances